Glutamate‐Dopamine Cotransmission and Reward Processing in Addiction

Abstract

While Dale's principle of "one neuron, one neurotransmitter" has undergone revisions to incorporate evidence of the corelease of atypical neurotransmitters such as neuropeptides, the corelease of classical neurotransmitters has only recently been realized. Surprisingly, numerous studies now indicate that the corelease of neurotransmitters in the mammalian central nervous system is not an obscure and rare phenomenon but is widespread and involves most classical neurotransmitters systems. However, the suggestion that glutamate can be coreleased with dopamine (DA) has remained controversial. Furthermore, glutamate-DA cotransmission has not yet been seriously considered in the context of the neurocircuitry of addiction. If glutamate is in fact coreleased with DA as some evidence now suggests, this may have significant implications for advancing our understanding of the interactive role that these 2 neurotransmitters play in cognitive and reward processes. In this commentary, we review the evidence for and against glutamate as a cotransmitter and discuss the potential role of glutamate-DA corelease in addiction. In particular, we describe a recently proposed model in which coreleased glutamate transmits a temporally precise prediction error signal of reward described by Schultz et al., whereas the function of coreleased DA is to exert prolonged modulatory influences on neuronal activity. In addition, we suggest that as alcohol consumption transitions from recreational use to addiction, there is a corresponding transition in the reward valence signal from better than predicted to worse than predicted.

Mesocorticolimbic Glutamatergic Pathway

“…Both classes of A10-glutamate neurons innervate the PFC and the nAcc; thus, we propose that in addition to the well-recognized mesocorticolimbic DA-only and GABA-only pathways, there exist parallel mesocorticolimbic glutamate-only and glutamate-DA pathways. Our documentation of mesocorticolimbic glutamate pathways in the adult rat may provide the theoretical background to experimentally advance the suggestion that glutamatergic signaling from the VTA may play a role in a fast neurotransmission of salient stimuli (Lapish et al, 2006(Lapish et al, , 2007. , and RLi.…”

Why Should We Keep the Cerebellum in Mind When Thinking About Addiction?

“…It has been demonstrated, however, that complex interactions between glutamatergic inputs to the basal ganglia and the dopamine system are critically involved in this long-term drug-induced neuroplasticity [58,59,60,61,62,63,64,65]. Now it is well-known that changes in glutamate transmission, including alterations in the structure and function of glutamate receptors and glutamate release mediate the effects of addictive drugs [58,59,64,65,66,67,68].…”

“…The stimulatory effects of drugs of abuse on locomotion and the subsequent progressive increase in this effect known as sensitization are both regulated by ionotropic (iGluR) and metabotropic (mGluR) glutamate receptors in the glutamate synapses of the nucleus accumbens (Nacc) and the ventral tegmental area (VTA) [65,66,67,68]. Moreover, modifications of postsynaptic proteins associated with glutamate intracellular signalling pathways were shown to be linked to drug-induced neuroplasticity and to contribute to the uncontrollable drive to seek drugs [61,62,63,69,70,71].In addition, recent findings support the participation of the endocannabinoid system in the common neural networks underlying drug-induced neuroplasticity and thereby, drug addiction [71]. The endocannabinoid retrograde control has been observed after synaptic activation of glutamate and dopamine receptors [73,74].…”

The role of glutamate and its receptors in mesocorticolimbic dopaminergic regions in opioid addiction

“…Morphological studies showed that there existed axon-axon synapses of glutamate and DA in mPFC, the ventral striatum and the NAc, providing the morphological evidence for the interaction between glutamate and DA in the mesocorticolimbic dopaminergic pathway (Bouyer et al, 1984;Goldman-Rakic, 1999). Anatomical and electrophysiological evidence indicates that glutamate can be co-released with DA and induce long-term regulation on the plasticity (Lapish et al, 2006). Local application of glutamate can enhance the release of DA in the NAc (Youngren et al, 1993;Svensson et al, 1994).…”